Discovery of Tetrahydropyrazolopyrimidine Carboxamide Derivatives As Potent and Orally Active Antitubercular Agents

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• 作者：Fumiaki Yokokawa ; Gang Wang ; Wai Ling Chan ; Shi Hua Ang ; Josephine Wong ; Ida Ma ; Srinivasa P S Rao ; Ujjini Manjunatha ; Suresh B Lakshminarayana ; Maxime Herve ; Cyrille Kounde ; Bee Huat Tan ; Pamela Thayalan ; Seow Hwee Ng ; Mahesh Nanjundappa ; Sindhu Ravindran ; Peck Gee ; Maria Tan ; Liu Wei ; Anne Goh ; Pei-Yu Chen ; Kok Sin Lee ; Chen Zhong ; Trixie Wagner ; Ina Dix ; Arnab K. Chatterjee ; Kevin Pethe ; Kelli Kuhen ; Richard Glynne ; Paul Smith ; Pablo Bifani ; Jan Jiricek
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：May 9, 2013
• 年：2013
• 卷：4
• 期：5
• 页码：451-455
• 全文大小：266K
• 年卷期：v.4,no.5(May 9, 2013)
• ISSN：1948-5875

文摘

Tetrahydropyrazolo[1,5-a]pyrimidine scaffold was identified as a hit series from a Mycobacterium tuberculosis (Mtb) whole cell high through-put screening (HTS) campaign. A series of derivatives of this class were synthesized to evaluate their structure鈥揳ctivity relationship (SAR) and structure鈥損roperty relationship (SPR). Compound 9 had a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse efficacy model, achieving a reduction of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. Thus, compound 9 is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB.

Keywords:

Antituberculosis; tetrahydropyrazolo[1,5-a]pyrimidine; structure鈭抋ctivity relationship; structure鈭抪roperty relationship